1. LRRK2 is a novel regulator of NFAT that modulates the severity of inflammatory bowel disease. Inflammatory bowel disease (IBD), which is generally thought to develop from a dysregulated immune response to the gut luminal biota, includes two major forms: Crohns disease (CD) and ulcerative colitis. Both genetic and environmental factors contribute to the development of CD1. Genome-wide association studies (GWAS) for Crohns disease have identified over 40 susceptibility loci2-4. The large number of the susceptibility genes likely reflects the complexity of the inflammatory process taking place along the gastrointestinal tract in IBD. The lymphoid tissue within the gastrointestinal tract constantly encounters normal commensal microbiota as well as potentially pathogenic bacteria;hence it is critical in this location to maintain a delicate balance between immune responsiveness and tolerance. Research on the susceptibility genes identified by GWAS has exemplified this concept, and yielded important insights into the pathogenesis of IBD. For example, the regulatory function of Treg cells, the involvement of autophagy, and IL23/IL23R signaling events have been implicated in IBD5. Despite this progress, the majority of susceptibility genes have no known mechanism to explain their involvement with CD. We investigated the role of LRRK2 in IBD and the underlying molecular mechanism. Various experimental murine models have been established to study the roles of innate and adaptive immune systems in the pathogenesis of IBD. Given the predominant expression of LRRK2 in innate immune cells but not in T cells21, dextran sulfate sodium (DSS) induced colitis was used in our study. Acute colitis induced by DSS depends on the innate immune system, because it occurs in severe combined immunodeficiency (SCID) mice which lack B and T lymphocytes22. Here we show that LRRK2 deficiency exacerbated colitis in mice treated with DSS. We searched for potential mediators of the effect using data from a RNAi screen in D. Melanogaster and found that LRRK2 was an interactor with NFAT. Examining this connection biochemically, we found that LRRK2 restrained NFAT1 in the cytoplasm within the NRON complex and inhibited NFAT1 activation. We also determined that LRRK2 did not alter NFAT1 phosphorylation but instead potently modulated cytoplasmic retention and the interaction between NFAT1 and the NRON complex in response to selected inducers such as lipopolysaccharide (LPS). Finally, a LRRK2 risk allele associated with CD in humans resulted in subtly reduced LRRK2 protein levels and delicately enhanced NFAT activity consistent with its role as part of a multifactorial susceptibility to human IBD. Collectively, our data demonstrate that LRRK2 negatively regulates NFAT-driven innate immune responses in myeloid cells and that lower levels of LRRK2 in humans provides a molecular insight into how this protein can contribute to an increased risk of CD. Future studies will address the involvement of LRRK2/NFAT pathway in the potential microgliosis and neurodegeneration in the brain. * The manuscript of the above data has been accepted by Nature Immunology. 2. Upregulation of Leucine-rich Repeat Kinase 2 Expression in Sporadic Parkinson Disease involves Specific MicroRNA. LRRK2 has been implicated in the progression of sporadic Parkinson Disease (PD). However, the mechanisms regulating LRRK2 protein expression and function in the brains of patients with sporadic PD remain to be determined. Here we show that the expression of LRRK2 protein is significantly increased in the brains of patients with sporadic PD. Moreover, we found a significant inverse-correlation between the expression of LRRK2 and microRNA-205 (miR-205) in the PD brains. The expression of LRRK2 and miR-205 were also dynamically regulated and inversely correlated in multiple regions of the brain as mice aged, suggesting a potential post-transcriptional regulatory role of miR-205 in modulating LRRK2 expression. Indeed over-expression of miR-205 suppressed the expression of LRRK2 in both cell lines and primary neuronal cultures, as well as rescued the neurite growth defects induced by over-expressing the PD-related LRRK2 R1441G mutation. In summary, we demonstrate that LRRK2 protein is up-regulated in the brains of patients with sporadic PD possibly due to down-regulation of miR-205. Our findings also suggest that over-expression of miR-205 may help to suppress the pathogenic elevation of LRRK2 in the brains of patients with PD. * The utility of miR-205 as a biomarker and therapeutic target has been submitted for patent application. * The manuscript of miR-205 data is under the final revision by Brain. 3. Deposition of LRRK2 WT and G2019S transgenic and LRRK2 knockout mice in the JAX for public access. JAX Mice Database - 012441 C57BL/6J-Tg(tetO-LRRK2*G2019S)E3Cai/J JAX Mice Database - 012449 TC57BL/6J-Tg(teto-LRRK2)C7874Cai/J JAX Mice Database - 012453 B6.129X1(FVB)-Lrrk2tm1.1Cai/J